Chronic Kidney Disease in a Large National Human Immunodeficiency Virus Treatment Program.

Tenofovir disoproxil fumarate (TDF) is associated with a risk of chronic kidney disease (CKD), especially in Asian populations. Data from the Thai national health insurance system was used to assess CKD incidence in patients receiving antiretroviral therapy in real-world practice. We analyzed data from patients who initiated one of the following first-line regimens: zidovudine + lamivudine + nevirapine (AZT + 3TC + NVP); zidovudine + lamivudine + efavirenz (AZT + 3TC + EFV); tenofovir + lamivudine + nevirapine (TDF + 3TC + NVP); tenofovir + lamivudine/emtricitabine + efavirenz (TDF + 3TC/FTC + EFV); and tenofovir +lamivudine +lopinavir/ritonavir (TDF + 3TC + LPV/r). CKD was defined as glomerular filtration rate <60 mL/min/1.73 m2 for >3 months, or a confirmed 2010 WHO diagnosis (ICD-10 code N183, N184, or N185). Death competing risk survival regression models were used. Among 27,313 participants, with a median age of 36.8 years and median follow-up of 2.3 years, 245 patients (0.9%) were diagnosed with CKD (incidence 3.2 per 1000 patient-years; 95% CI 2.8−3.6). Compared with patients receiving AZT + 3TC + NVP, the risk of CKD measured by adjusted sub-distribution hazard ratio (aSHR) was 6.5 (95% CI 3.9−11.1) in patients on TDF + 3TC + LPV/r, 3.8 (95% CI 2.3−6.0) in TDF + 3TC + NVP, and 1.6 (95% CI 1.2−2.3) in TDF + 3TC/FTC + EFV. Among patients receiving TDF, compared with those receiving TDF + 3TC/FTC + EFV, the aSHR was 4.0 (95% CI 2.3−6.8) in TDF + 3TC + LPV/r and 2.3 (95% CI 1.4−3.6) in TDF + 3TC + NVP. TDF was associated with an increased risk of CKD, especially when combined with LPV/r or NVP.

Recommended First-Line Antiretroviral Therapy Regimens and Risk of Diabetes Mellitus in HIV-Infected Adults in Resource-Limited Settings.

OBJECTIVE: The use of some antiretroviral drugs has been associated with a higher risk of diabetes mellitus (DM) in HIV-infected patients, but the risk associated with antiretroviral drug combinations remains unclear. We investigated the association between first-line antiretroviral therapy (ART) regimens, recommended by the World Health Organization (WHO) in 2016, and the risk of DM in adults. METHOD: We selected all HIV-infected adults within the Thai National AIDS Program who started a first-line ART regimen consisting the following between October 2006 and September 2013: zidovudine+lamivudine+nevirapine; tenofovir disoproxil fumarate (TDF)+lamivudine+nevirapine; zidovudine+lamivudine+efavirenz; TDF+lamivudine/emtricitabine+efavirenz; zidovudine+lamivudine+ritonavir-boosted lopinavir (LPV/r); or TDF+lamivudine+LPV/r. Diagnosis of DM was defined as having at least 2 of the following characteristics: fasting plasma glucose ≥126 mg/dl, 2010 WHO ICD-10 codes E11-E14, or prescription of antidiabetic drugs. To identify ART regimens associated with DM, we used competing risks regression models that considered mortality without DM as a competing event and adjusted for sex, age, pancreas disease, and stratified by groups defined by a score summarizing the propensity to receive a specific first-line ART regimen. RESULTS: Data from 35 710 adults (49.1% male; median age, 35.0 years; median follow-up, 2.0 years) were included. In the multivariable analysis with zidovudine+lamivudine+nevirapine as the reference group, a higher risk of DM was observed with TDF+lamivudine/emtricitabine+efavirenz (adjusted sub-distribution hazard ratio [aSHR], 1.6; 95% confidence interval [CI], 1.3-1.9), zidovudine+lamivudine+efavirenz (aSHR, 2.0; 95% CI, 1.7-2.3), and TDF+lamivudine+LPV/r (aSHR, 2.7; 95% CI, 1.9-3.9). CONCLUSIONS: Several of the WHO recommended ART regimens, particularly tenofovir + lamivudine +LPV/r and regimens containing efavirenz, may be associated with an increased risk of DM.

Incidence and clinical outcomes of diabetes mellitus in HIV-infected adults in Thailand: a retrospective cohort study.

BACKGROUND: Since 2005, Thailand has scaled up one of the largest antiretroviral treatment (ART) programs in South East Asia. Although diabetes mellitus (DM) incidence is increasing in low and middle-income countries, its burden and contributing factors in the HIV infected population are not well known. METHODS: Using the Thai National AIDS Program data over a period of 8-years, we identified patients diagnosed with DM based on the following records: 1) fasting plasma glucose equal to or greater than 126 mg/dl following the 2013 American Diabetes Association criteria or 2) diagnosis codes E11-E14 of the 2010 WHO International Classification of Diseases, or 3) anti-diabetic drugs. Incidence was the number of new cases divided by that of person-years of follow-up (PYFU). Competing risks survival regression, treating death without DM as a competing event, was used to identify factors associated with DM. The risk of death in patients diagnosed with DM was estimated using Cox regression models. RESULTS: Data of 763,666 PYFU from 199,707 patients (54.2% male; median age 36.2 years at registration with the program) were available and 8383 cases were diagnosed with DM, resulting in an incidence rate of 11.0 per 1000 PYFU. New DM diagnosis was more likely in men (adjusted sub-distribution hazard ratio 1.2), older patients (compared to patients 18 to 34 years old: 1.8 for 35 to 44; 3.0 for 45 to 59; 3.8 for ≥60), and if ART was initiated (1.3). In 2014, 1313 (16.6%) of 7905 diabetic patients had DM complications (11.5% microvascular complications and 6.9% macrovascular complications). Patients diagnosed with DM were at higher risk of death compared to the others. CONCLUSIONS: DM incidence was higher in this Thailand cohort of HIV infected adults than in the general population. Risk factors were similar to those in the general population, in addition to starting ART.

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B.

BACKGROUND: Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants' receiving hepatitis B immune globulin. METHODS: In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)-positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)-positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group). RESULTS: From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log10 IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29). CONCLUSIONS: In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .).

Need for Internal Medicine Subspecialists in Thailand.

Background: Matching supply side of the Internal Medicine (IM) subspecialists to the demand for complex medical care at referral medical centers would lead to more efficient health system management and ultimately optimal clinical outcome. The second decade of the universal health coverage policy in Thailand has raised the awareness on how to reach equitable utilization goals of good quality medical services, while barriers of accession have been removed. More accurate evidence-based human resource planning is timely needed. Objective: To estimate the number of the ten subspecialists in internal medicine (neurologist, cardiologist, endocrinologist, gastroenterologist and hepatologist, nephrologist, hematologist, oncologist, rheumatologist, pulmonologist, and infectious disease specialist) needed for complex medical care based on the workload in the year 2013. Material and Method: The present study applied a needs assessment model with evidence-based approach. Claimed data of inpatients in the year 2013 from the three government insurance schemes (the Civil Servant Medical Benefit, the Social Security and the Universal Health Coverage schemes), and out-patient data from Universal Coverage System were used to estimate demand for subspecialists. The Human Resource Working Group of the Royal College of Physicians of Thailand agreed on the conceptual framework to estimate the need for ten subspecialists based on clinical activities of outpatient consultations, inpatient ward rounds and non-operating room procedures on medical cases of respective diagnosis related group with severe and catastrophic comorbidities and complications by the Thai-DRG version 5. Representatives from the Associations of IM subspecialties approved the lists of ICD-10 diagnosis and ICD-9-CM procedure codes specific to each subspecialist care and proposed assumptions on rates of consultations from other specialists. Surveys were done to subspecialists in 6 major provincial clusters and representatives from IM subspecialty Associations asking time spent on main activities of patient care. The number of full-time-equivalent (FTE) subspecialists needed was calculated by multiplying the clinical workloads measured in minutes spent for each activity (ward round, ward work, inpatient and outpatient consultations) to get the total time needed, then divided by the available time for clinical activity of one subspecialist. Results: From 5.9 million inpatient discharges in the year 2013, primary responsibility of patients in respective severe and catastrophic DRGs related to specific subspecialist workloads were summed up for teaching hospitals and regional hospitals ranging from as lowest the 2,849 cases for rheumatology to the highest 24,610 cases for gastroenterology and hepatology. The number of inpatient non-operating room procedures by ICD-9-CM as listed by IM subspecialty Associations ranged from 8 times for endocrinologists to 22,927 times for cardiologists for the whole year. Of ten subspecialists, the estimated numbers of cardiologist, nephrologist, neurologist, gastroenterologist and hepatologist, endocrinologist, oncologist, rheumatologist, hematologist, pulmonologist and infectious disease subspecialist needed at teaching and regional hospitals were 516, 241; 345, 144; 312, 143; 195, 124; 189, 45; 137, 170; 90, 47; 96, 111; 203, 87 and; 129, 44 respectively according to the workload recorded in the year 2013. The forecast FTE found the overall gap of discrepancy at 7 percent. If the distributions of these subspecialists in public and private hospitals were taken into account, the gap of discrepancy in public hospitals increased to 47 percent. Conclusion: The demand-based forecast for the number of subspecialist needed was made possible with assumptions on conceptual framework for case selection, the rates of consultation and time-spent related to activities of patient care. The estimated numbers of subspecialists were anticipated far from optimum since the workload in the year 2013 was derived as a consequence of pre-existing suboptimal infrastructure of healthcare system. In addition, the deficit of subspecialists may increase in the near future when highly efficient, non- or mildly invasive, time-consuming procedures of acute illness increase. Sustainable matching demand and supply of human resource for health needed further validations of these assumptions.

Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral load for the prevention of MTCT of HBV. METHODS: The study is a phase III, multicenter (17 sites in Thailand), placebo-controlled, double-blind, randomized 1:1, two-arm clinical trial of TDF 300 mg once daily versus placebo among pregnant women from 28 weeks' gestation through 2-month post-partum. All infants receive HBIg at birth, and a hepatitis B (HB) vaccination series according to Thai guidelines: birth, and age 1, 2, 4 and 6 months. Participant women at study entry must be age ≥18 years, hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg) positive, have alanine aminotransferase (ALT) level < 30 IU/L at screening (confirmed < 60 IU/L pre-entry), negative hepatitis C serology, creatinine clearance >50 mL/min, and no history of anti-HBV antiviral treatment. The target sample size of 328 mother/infant pairs assumed 156 evaluable cases per arm to detect a ≥9 % difference in MTCT transmission (3 % experimental arm versus 12 % placebo arm) with 90 % power. Mothers and infants are followed until 12 months after delivery. The primary infant endpoint is detection of HBsAg, confirmed by detection of HBV DNA at six months of age. Secondary endpoints are maternal and infant adverse events, acute exacerbations of maternal hepatitis B disease (ALT >300 IU/L, defined as a "flare") following discontinuation of study treatment, infant HBV infection status and growth up to 12 months of age. DISCUSSION: The results of this randomized trial will clarify the efficacy and safety of a short course of antiviral treatment to prevent mother-to-child transmission of HBV and inform international guidelines. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01745822 .

Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial.

BACKGROUND: Thai patients with HIV have higher exposure to HIV protease inhibitors than do white people and dose reduction might be possible. We compared the efficacy of low-dose with standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai patients with HIV. METHODS: In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years or older who were receiving ritonavir-boosted protease-inhibitor-based antiretroviral therapy (ART) with HIV plasma viral loads of less than 50 copies per mL, an alanine aminotransferase concentration of less than 200 IU/L, and a creatinine clearance of at least 60 mL/min from 14 hospitals in Thailand. We excluded patients who had active AIDS-defining disease or opportunistic infections, had a history of an HIV viral load of 1000 copies per mL or more after 24 weeks of any ritonavir-boosted protease-inhibitor-based ART, used concomitant medications that could interact with the study drugs, were pregnant or lactating, had illnesses that might change the effect of the study drugs, or had a history of sensitivity to the study drugs. A biostatistician at the study coordinating centre randomly allocated patients (1:1) to switch the protease inhibitor for oral atazanavir 200 mg and ritonavir 100 mg or for atazanavir 300 mg and ritonavir 100 mg once daily, both with two nucleoside or nucleotide reverse transcriptase inhibitors at recommended doses. Randomisation was done with a minimisation schedule, stratified by recruiting centre, use of tenofovir, and use of indinavir as a component of the preswitch regimen. The primary endpoint was the proportion of patients with viral loads of less than 200 copies per mL at week 48, and we followed up patients every 12 weeks. Treatments were open label, the non-inferiority margin was -10%, and all patients who received at least one dose of study medication were analysed. This trial is registered with ClinicalTrials.gov, number NCT01159223. FINDINGS: Between July 6, 2011, and Dec 23, 2013, we randomly assigned 559 patients: 279 to receive atazanavir 200 mg and ritonavir 100 mg (low dose) and 280 to atazanavir 300 mg and ritonavir 100 mg (standard dose). At week 48, 265 (97·1%) of 273 in the low-dose group and 267 (96·4%) of 277 in the standard-dose group had viral loads of less than 200 copies per mL (difference 0·68; 95% CI -2·29 to 3·65). Seven (3%) of 273 in the low-dose group and 21 (8%) of 277 in the standard-dose group discontinued their assigned treatment (p=0·01). 46 (17%) of 273 participants in the low-dose group and 97 (35%) of 277 in the standard-dose group had total bilirubin grade 3 or higher toxicity (≥3·12 mg/dL; p<0·0001). INTERPRETATION: A switch to low-dose atazanavir should be recommended for Thai patients with well controlled HIV viraemia while on regimens based on boosted protease inhibitors. FUNDING: The National Health Security Office and Kirby Institute for Infection and Immunity in Society.

New-Onset Diabetes and Antiretroviral Treatments in HIV-Infected Adults in Thailand.

BACKGROUND: Use of several antiretrovirals (ARVs) has been shown to be associated with a higher risk of diabetes in HIV-infected adults. We estimated the incidence of new-onset diabetes and assessed the association between individual ARVs and ARV combinations, and diabetes in a large cohort in Thailand. METHODS: We selected all HIV-1-infected, nondiabetic, antiretroviral-naive adults enrolled in the Program for HIV Prevention and Treatment cohort (NCT00433030) between January 2000 and December 2011. Diabetes was defined as confirmed fasting plasma glucose ≥ 126 mg/dL or random plasma glucose ≥ 2 00 mg/dL. Incidence was the number of cases divided by the total number of person-years of follow-up. Association between ARVs and ARV combinations, and new-onset diabetes was assessed using Cox proportional hazards models. RESULTS: Overall, 1594 HIV-infected patients (76% female) were included. Median age at antiretroviral therapy initiation was 32.5 years. The incidence rate of diabetes was 5.0 per 1000 person-years of follow-up (95% confidence interval: 3.8 to 6.6) (53 cases). In analyses adjusted for potential confounders, exposure to stavudine + didanosine [adjusted hazard ratio (aHR) = 3.9; P = 0.001] and cumulative exposure ≥ 1 year to zidovudine (aHR = 2.3 vs. no exposure; P = 0.009) were associated with a higher risk of diabetes. Conversely, cumulative exposure ≥ 1 year to tenofovir (aHR = 0.4 vs. no exposure; P = 0.02) and emtricitabine (aHR = 0.4 vs. no exposure; P = 0.03) were associated with a lower risk. CONCLUSIONS: The incidence of diabetes in this predominantly female, young, lean population was relatively low. Although stavudine and didanosine have now been phased out in most antiretroviral therapy programs, our analysis suggests a higher risk of diabetes with zidovudine, frequently prescribed today in resource-limited settings.

Plasma and Intracellular Pharmacokinetics of Tenofovir Disoproxil Fumarate 300 mg Every 48 Hours vs 150 mg Once Daily in HIV-Infected Adults With Moderate Renal Function Impairment.

BACKGROUND: The approved tenofovir disoproxil fumarate (TDF) dose of 300 mg every 48 hours for adults with moderate renal impairment is often confusing and inconvenient. Using a new TDF formulation, we compared the pharmacokinetics of the standard dose with a dose of 150 mg once daily in HIV-infected adults. METHODS: This was an open-label pharmacokinetic study. Virologically suppressed HIV-infected adults with a creatinine clearance 30 to <50 mL/minute receiving TDF 300 mg every 48 hours as part of a nonnucleoside reverse transcriptase inhibitor (NNRTI)- or lopinavir/ritonavir (LPV/r)-based regimen were enrolled. Intensive 48-hour blood sampling for pharmacokinetic assessment was performed at enrollment, after which the TDF dose was changed to 150 mg once daily. Two weeks later, 24-hour blood sampling was performed; subjects then returned to the standard dose. Tenofovir (TFV) pharmacokinetic parameters were calculated using a noncompartmental analysis. RESULTS: Forty adults (55% female) were enrolled: 20 receiving NNRTI-based and 20 receiving LPV/r-based treatment. Median age was 56 years (range, 44-65 years), weight 51 kg (range, 38-80 kg), and creatinine clearance 43.9 mL/minute (range, 30.9-49.7 mL/minute). The TFV geometric mean ratio of the area under the curve (AUC0-48 h) for every 24 hours vs every 48 hours was 1.09 (90% confidence interval [CI], .98-1.22) and 1.00 (90% CI, .92-1.09) for patients receiving NNRTI- and LPV/r-based treatment, respectively. Concomitant LPV/r use markedly increased TFV plasma concentrations, and AUC0-48 h was 67% higher with the standard dose, whereas no differences in intracellular TFV diphosphate concentrations were observed. All subjects remained virologically suppressed, and no drug-related adverse events were reported. CONCLUSIONS: TDF 150 mg every 24 hours provides comparable systemic exposure to the standard dose of 300 mg every 48 hours in patients with moderate renal impairment. CLINICAL TRIALS REGISTRATION: NCT01671982.

Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning.

Ergotism is a toxic condition resulting from overexposure to the ergot compounds produced by various fungi of the genus Claviceps. Traditionally, such exposure was due to ingestion of infected grains, but long-term or excessive use of medications containing ergot derivatives or drug-drug interactions between these medications can result in ergotism. Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4). Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism. A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997 (most recently reviewed by Frohlich et al).

Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand.

BACKGROUND: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand. METHODS AND FINDINGS: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported. CONCLUSIONS: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.

Extended evaluation of the virologic, immunologic, and clinical course of volunteers who acquired HIV-1 infection in a phase III vaccine trial of ALVAC-HIV and AIDSVAX B/E.

BACKGROUND: The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection. METHODS: CD4(+) T-cell counts and HIV viral load (VL) were measured serially. The primary analysis evaluated vaccine efficacy (VEP) as the percent reduction (vaccine vs placebo) in cumulative probability of a primary composite endpoint of clinical and CD4(+) count components at prespecified time points after infection. Secondary analyses of biomarker-based endpoints were assessed using marginal mean and linear mixed models. RESULTS: There were 61 endpoints in the modified intent-to-treat cohort (mITT; n = 114). There was no evidence for efficacy at 30, 42, 54, and 60 months in the mITT and per protocol (n = 90) cohorts. Estimated VEP (mITT) was15.8% (-21.9, 41.8) at 60 months postinfection. There was weak evidence of lower VL and higher CD4(+) count at 60 and 66 months in the vaccine group. Lower mucosal VL was observed among vaccine recipients, primarily in semen (P = .04). CONCLUSIONS: Vaccination did not affect the clinical course of HIV disease after infection. A potential vaccine effect on the genital mucosa warrants further study.

A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR study.

BACKGROUND: Data informing the use of boosted protease inhibitor (PI) monotherapy as second-line treatment are limited. There are also no randomized trials addressing treatment options after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimens. METHODS: HIV-infected subjects ≥18 years, with HIV RNA≥1,000 copies/ml while using NNRTI plus 2 NRTIs, and naive to PIs were randomized to lopinavir/ritonavir (LPV/r) 400/100 mg twice daily monotherapy (mono-LPV/r) or tenofovir disoproxil fumarate (TDF) once daily plus lamivudine (3TC) twice daily plus LPV/r 400/100 mg twice daily (TDF/3TC/LPV/r) at nine sites in Thailand. The primary outcome was time-weighted area under curve (TWAUC) change in HIV RNA over 48 weeks. The a priori hypothesis was that the mono-LPV/r arm would be considered non-inferior if the upper 95% confidence limit in TWAUC mean difference was ≤0.5 log(10) copies/ml. RESULTS: The intention-to-treat (ITT) population comprised 195 patients (mono-LPV/r n=98 and TDF/3TC/LPV/r n=97): male 58%, baseline mean (sd) age of 38 (7) years, CD4(+) T-cell count of 204 (135) cells/mm(3) and HIV RNA of 4.1 (0.6) log(10) copies/ml. The majority had HIV-1 recombinant CRF01_AE infection, and thymidine analogue mutation (TAM)-2 was 3× more common than TAM-1. At 48 weeks, the difference in TWAUC HIV RNA between arms was 0.15 (95% CI -0.04, 0.33) log(10) copies/ml, consistent with our definition of non-inferiority. However, the proportion with HIV RNA<50 copies/ml was significantly lower in the mono-LPV/r arm: 61% versus 83% (ITT, P<0.01). Baseline HIV RNA≥5 log(10) copies/ml (P<0.001) and mono-LPV/r use (P=0.003) were predictors of virological failure. Baseline genotypic sensitivity scores ≥2 and TAM-2 were associated with better virological control in subjects treated with the TDF-containing regimen. CONCLUSIONS: In PI-naive patients failing NNRTI-based first-line HAART, mono-LPV/r had a significantly lower proportion of patients with HIV RNA<50 copies/ml compared to the TDF/3TC/LPV/r treatment. Thus, mono-LPV/r should not be recommended as a second-line option.

Long term outcomes of nevirapine containing antiretroviral therapy at a center in Thailand.

This retrospective cohort study was conducted at Chon Buri Hospital, Thailand, to determine the long term outcomes of patients taking Nevirapine (NVP) containing antiretroviral therapy (ART). Patients taken NVP at least 5 years were included. Two hundred eighty-five patients met inclusion criteria and were included in the study. The median age of patients was 35 years; the median baseline CD4 was 66 cells/mm3 and the median follow-up was 7 years. Ninety-two point four percent and 90.2% of patients achieved virological success at year 5 and year 7, respectively. The median rise in CD4 count from baseline to year 5 was 354 cells/mm3 (IQR 235.5-487 cells/mm3) and at year 7 was 387 cells/mm3 (IQR 272-557 cells/mm3). Thirty-eight point eight percent of patients had a CD4 count > or = 500 cells/mm3 at year 5 and 41.6% at year 7. Rash/hypersensitivity occurred in 2 patients after 5 years and was transient. Elevated liver enzymes occurred in 5 patients after 5 years. NVP-containing ART yielded high virological-success rates. Long-term immunological response, safety and durability were also high.

Histoplasmosis and penicilliosis among HIV-infected Thai patients: a retrospective review.

Histoplasmosis and penicilliosis are fungal infections with similar clinical presentation and laboratory findings that were reported mainly in the era prior to highly active antiretroviral therapy. We conducted a retrospective review at two hospitals in Central Thailand of the medical records of HIV-positive patients with microbiologic evidence of histoplasmosis or penicilliosis between January 2003 to September 2007 when antiretrovirals became widely available in Thailand. Fifty patients met inclusion criteria; 36 had histoplasmosis, and 14 had penicilliosis. Symptoms and laboratory findings on presentation were similar between the two infections except for a greater incidence of tachypnea and neutropenia among patients with histoplasmosis (both p < 0.05). For histoplasmosis, blood culture had a significantly lower yield for detecting infection compared to tissue microscopic examination highlighting the importance of obtaining tissue for diagnosis (p < 0.05).

Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum.

BACKGROUND: The impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6-12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr(-1)·mL(-1)) and a trough concentration of 1 mcg/mL. RESULTS: Twenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9-42.9) years, weight 69.0 (40-130) kg, and gestational age 32.9 (30.1-38.7) weeks. Median (range) EFV AUC(0-24), C(max), and C(24 hours) were 55.4 mcg·hr(-1)·mL(-1) (13.5-220.3), 5.4 mcg/mL (1.9-12.2), and 1.6 mcg/mL (0.23-8.13), respectively. EFV AUC and C(max) did not differ during pregnancy and postpartum but C(24 hours) was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37-0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported. CONCLUSIONS: Changes in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.

Monitoring of Renal Function among HIV-Infected Patients Receiving Tenofovir in a Resource-Limited Setting.

The use of tenofovir disoproxil fumarate (TDF) is supposed to be increased in a resource-limited setting due to the changing of the guidelines. TDF-associated renal function declines among HIV-infected patients were defined by an increase of serum creatinine (SCr) >1.5 times, a 25% decrease in calculated creatinine clearance (CCrCl), or an estimated glomerular filtration rate (eGFR) from the baseline. Of all, 99% were antiretroviral treatment (ART)-experienced patients. At the 30th month, 19 (5.3%), 53 (14.9%), and 63 (17.7%) patients had renal function decline as defined by the above criteria with an incidence of 4.5, 12.5, and 14.6/100 person-year. A proportion of patients with a renal function decline detected by CCrCl or eGFR criteria was not different (P = .301), whereas, it differed from that detected by SCr criteria (P < .001). In conclusion, we encourage either CCrCl or eGFR calculations in monitoring renal function decline among HIV-infected patients receiving TDF in resource-limited settings.

Influence of body weight on achieving indinavir concentrations within its therapeutic window in HIV-infected Thai patients receiving indinavir boosted with ritonavir.

Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.

Incidence and risk factors for tenofovir-associated renal function decline among Thai HIV-infected patients with low-body weight.

OBJECTIVES: we aimed at determining the incidence and factors for TDF-associated renal function decline among Thai HIV-infected patients. METHODS: retrospective and prospective cohort studies were conducted. We enrolled HIV-infected adults who had initiated TDF. Renal function decline that was defined by a decrease of 25% in glomerular filtration rate (GFR) from the baseline. Factors associated with the renal function decline were determined. RESULTS: a total of 405 patients with a median (IQR) body weight of 56.5 (50.5-65.0) kg were enrolled. All but four (99%) were antiretroviral treatment-experience patients. A median (IQR) duration of receiving TDF was 16 (8-21) months. Of these, 78 (19.3%) patients had a 25% decrease in GFR with the incidence rate of 16.2 per 100 person-years. By Kaplan-Meier survival analysis, median time to a 25% decrease in GFR was 28 [95% confidence interval (CI) 25.2-30.8] months. By multiple logistic regression, lower body weight [odds ratio (OR) 1.15 per 5 kg, 95% CI 1.00-1.33], lower body mass index (BMI) (OR 2.26 per 1 kg/m(2), 95% CI 1.74-2.94), baseline GFR (OR 1.62 per 10 ml/min/1.73m(2), 95% CI 1.39-1.88), protease inhibitor (OR 2.12, 95% CI 1.15-3.92), and nephrotoxic drug (OR 3.16, 95% CI 1.44-6.98) were statistically significant factors associated with a 25% decrease in GFR. CONCLUSIONS: the study revealed high incidence of TDF-associated renal function decline among patients with low-body weight and BMI. Additional risk factors were baseline GFR, receiving protease inhibitor, and nephrotoxic drugs. Close monitoring of renal function is warranted among patients with these risk factors.

Pregnancy outcomes among HIV-infected women undergoing antiretroviral therapy.

BACKGROUND: The use of antiretroviral drugs (ARV) to prevent mother-to-child HIV transmission (PMTCT) promises to be effective. However, limited data on the adverse effects of ARV among pregnant women and pregnancy outcomes have been reported in clinical practice. OBJECTIVES: This study aimed to assess adverse effects and outcomes among pregnant HIV-infected women receiving antiretroviral drugs for either antiretroviral therapy (ART) or PMTCT. STUDY DESIGN: This cohort study was at Chonburi Hospital, Thailand, in 2002-2006. RESULTS: A total of 246 pregnant HIV-infected women with the median age (range) of 27 (16-41) years were included in this study. ART was initiated in 16.3% for treatment during ANC, 66.7% for PMTCT during ANC, and 17.1% for PMTCT in labor. Adverse effects, especially anemia, were significantly associated with continuing combined ART in pregnancy (p<0.001). 88.9% delivered normal-term neonates. The prevalence of pre-term delivery was 10.2%. Overall, 24 adverse events from 21 pregnant women (8.5%) were noted. A significantly higher prevalence of pre-term delivery was noted in the groups continuing combined ART, or initiating of PMTCT during labor rather than ANC (p=0.02). The incidence of low Apgar scores was 3.6%, and these were associated with initiation of PMTCT during labor (p=0.004). CONCLUSION: Adverse ARV events were more numerous among the pregnant women who needed ART than PMTCT. ANC is beneficial and strongly recommended for all pregnant HIV-infected women for better pregnancy outcomes.